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P E R S P E C T I V E S
American College of Endocrinology
Pre-Diabetes Consensus Conference:
ZACHARY T. BLOOMGARDEN, MD
of variables such as LDL cholesterol al-lows considerably greater cardiovasculardisease prediction than available with IFG TheAmericanCollegeofEndocrinol- ratiosthatareconsideredimportantare andIGT,similartotheperformanceofthe
with an odds ratio of 1.5 only associated nized around a series of interrelated ques- Ͼ0.8. It should be noted, however, that new risk factor along with conventional the analysis to which Stern referred sim- ply noted the complexity of relative risk in establishing disease likelihood in an indi- vidual of a population with modest a pri- datasets showing the same characteristics.
ori disease risk, such that the population- “A considerable effort is required to im- attributable risk for a threefold increase in relative risk may be quite substantial.
have,” Stern said. An important barrier to to identifying pre-diabetes, noting that, of to be the greater usefulness of continuous health professionals tend to consider that rather than dichotomous risk scores.
they lack naturally occurring cut points, fore diabetes and that, of course, diabetes With the latter, sensitivity, specificity, he noted. In fact, however, cut points for established risk factors such as glucose, blood pressure, and lipids also tend to be “tweaks the cut point,” allowing one to arbitrary, as are the various criteria used clearly associated, for example, with in- optimize test behavior. He suggested that creased cardiovascular risk). Pre-diabetes that the notion of pre-diabetes as a condi- tion necessitating treatment requires care- state, the significance of which lies in its state is associated with future morbidity ability to predict adverse health outcomes and mortality, one should not use the par- for individuals diagnosed. As there is no adigm of treating illness in devising ap- epidemiologic study, his group calculated evidence that early intervention (prior to a diabetes risk score, showing it to be a diagnosis of diabetes) is better than late the adage “prediction is very difficult, es- better predictive approach than either im- intervention (after diabetes is present), he pecially about the future,” variously at- paired fasting glucose (IFG) (fasting glu- suggested that “it is a very profound ques- cose 100 –125 mg/dl) or impaired glucose tion” as to whether the concept of pre- pointed out that predictions applying to a diabetes should be applied to individuals.
Rather, he suggested, it needs to be dem- fasting glucose, systolic blood pressure, point glycemic intervention should begin; HDL cholesterol, BMI, and family history, strong clinical trial data for glucose inter- although Stern noted that ethnicity limits the degree to which the model can be gen- curve (AUC) a measure of the reliability of better ability to predict diabetes than ei- better than a flip of a coin to 1.0 for a completely reliable test (1). Relative risk emphasizing the need for evidence-basedprevention of diabetes and vascular com- ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● plications. She discussed the complex his- Zachary T. Bloomgarden, MD, is a practicing endocrinologist in New York, New York, and is affiliated with the Division of Endocrinology, Mount Sinai School of Medicine, New York, New York.
2008 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.
ciation (ADA) definitions of diabetes ac- org/licenses/by-nc-nd/3.0/ for details.
DIABETES CARE, VOLUME 31, NUMBER 10, OCTOBER 2008 Bloomgarden
(7.0 mmol/l/l) and 2-h post–75-g glucose glucose was found in analysis of the Ath- waist, insulin resistance, and hyperinsu- load levels Ն200 mg/dl (Ն11.1 mmol/l).
linemia (17). In the analysis, insulin resis- lower limit of IFG be reduced from 110 to 100 mg/dl, putting it in conflict with the diagnosis of diabetes (5). There are, then, betes risk: those based on direct measures result of heterogeneity between individu- Dekker reviewed the concept that there is heterogeneity in the degree to which dif- range. As with any condition, the bulk of given blood glucose concentration. In the of the differing definitions and the preva- Islington Diabetes Survey, only 19 – 41% lence of the (pre-) disease states so de- lations may be rather different from indi- was explained by the 2-h glucose (12).
Although a proposal is currently being ad- lowering agents or other drugs directed at an estimated average glucose (13), only a been studied in this fashion. There appear ages 50 –75 years, with follow-up evalua- with differing degrees of hemoglobin gly- cation potentially related to differences in and 2007 including oral glucose tolerance erythrocyte survival, different intracellu- associations from the Strong Heart Study, ing the WHO criterion with a cut point of erythrocyte permeability to glucose.
(More information on this point is present diabetes versus diabetes relationships to in a recent analysis of the topic of variabil- CVD. A caveat is the degree of interindi- vidual and interlaboratory variability in ers have reported a similar increase in IFG edly on retesting. She cited a study per- lower risk of diabetes than those satisfying the WHO criterion (7). In the Hoorn data- set, individuals with either IFG (based on quencies of 13 and 38%, respectively, for fasting glucose Ն110 mg/dl) or IGT alone IGT. Insulin resistance is a major determi- A1C is also associated with future risk of nant of type 2 diabetes and is almost al- both elevated fasting and 2-h glucose de- in people with IGT. Given its association with CVD risk, she suggested that effects diabetes, noting that its many definitions tolerance in 1998 and 2005 similarly sug- give rise to high variability in reported ciated with increase in the risks of diabe- tes (most but not all of which are due to for insulin resistance and analyzed rela- glucose as a factor) and CVD, with heter- Collaborative Analysis of Diagnostic Cri- the use of 2-h glucose without a threshold 4,549 American Indians ages 45–74 years for mortality, as the 2-h glucose increased from Յ3 to Ն11.1 mmol/l/l, while there is a definite difference in outcome for fasting (10). Similar evidence of greater associa- (using ADA criteria), 619 IGT, 1,420 pre- tion with mortality of 2-h than of fasting DIABETES CARE, VOLUME 31, NUMBER 10, OCTOBER 2008 Perspectives on the News
diabetic individuals in preventing diabe- NEWS FROM THE FOOD AND DRUG ADMINISTRATION
tes and in treating risk factors. Animportant question is whether, with a From time to time, new announcements by the FDA pertaining to aspects of diabetes more accurate measure of risk of diabetes, treatment will be highlighted in this section. those who subsequently develop diabeteswould show increased CVD risk before The FDA has indicated ongoing concern about the use of ezetimibe, announcing that it intended to investigate the report from the Simvastatin and Ezetimibe in in analysis of the Nurses’ Health Study Aortic Stenosis (SEAS) trial of a possible association between the use of Vytorin (18). Corollary questions include 1) and increased incidence of cancer. Cardiovascular risk was not reduced with the agent in the study of individuals with aortic stenosis.
logically) treat blood glucose elevations Expanding on its October 2007 report of 30 individuals receiving Byetta and before development of diabetes or to wait developing pancreatitis, the FDA announced that it had learned of six cases of for diabetes to develop before initiation of hemmorrhagic or necrotizing pancreatitis in patients receiving this agent, with all pharmacologic diabetes treatment and 2) requiring hospitalization and two dying. There are well-documented associations of pacreatitis with obesity, with dyslipidemia, and with diabetes itself, and pan- for pre-diabetic individuals. The clinical creatitis may be associated with use of many medicines given to diabetic patients, including sulfonylureas, ACE inhibitors/angiotensin receptor blockers, and di- questions are not available, although sur- uretics, such that the expected incidence among the more than 700,000 patients treated with Byetta might be double or more the expected pancreatitis rate of somewhere Ͼ0.01% in the general population—perhaps 150 cases. The reported 36 cases, then, represents an unknown fraction of those expected. One might, lead to specific characteristics of those then, question the FDA’s implication that Byetta increases the risk of pancreatitis, populations differing from those of other recognizing that while underreporting of adverse events to the agency might make any apparent grouping of events potentially serious, there may now be an opposite effect of the earlier announcement increasing such reporting.
be that this group “got fatter earlier . . .
[and that] some of the other populations Finally, the FDA announced that it has approved six manufacturers’ influenza aren’t as far along this continuum.” Phar- vaccines for the 2008-2009 season. Every year, 5-20% of the U.S. population gets influenza, more than 200,000 people are hospitalized from its complications, and there are ϳ36,000 flu-related deaths; vaccination of people with chronic medical conditions such as diabetes and of health care personnel is thus critical. The FDA newsletter pointed out that just 40% of health care workers in the United States risk ethnicity, those with IFG plus meta- receive an influenza vaccination (http://www.fda.gov/bbs/topics/NEWS/2008/ described by Stern, those satisfying a riskscore based on multiple markers.
half of this very high-risk population.
IFG, IGT, and pre-diabetes led to a three- fold increase in diabetes risk in the pop- ulation, leading Howard to conclude that, in this population, the GTT offered rela- in 57 and 69%, respectively, of those with tively little additional information to that available from fasting glucose. Triglycer- tively, of those with diabetes. Metabolic ide levels were ϳ105 in NGT, 140 in pre- the correlation of two fasting blood glu- diabetic, and 180 in diabetic men, with a greater age, BMI, and cigarette use, all of cose levels was 0.72 while that of two 2-h mean absolute differences of 4 and 17 mg/ syndrome doubled the risk of left ventric- altered in composition in states of dysme- and, perhaps, that it might be reasonable tabolism, becoming more atherogenic.
creased risk of CVD events with metabolic to follow this serially for adequate diagno- creased with pre-diabetes, the prevalence of carotid plaque was increased in diabe- tes but not in pre-diabetes, and echocar- tients, considering the great deal of data circumference (21) predict insulin resis- nary artery disease and stroke risks were, DIABETES CARE, VOLUME 31, NUMBER 10, OCTOBER 2008 Bloomgarden
(22). An interesting consideration is “met- abolic fitness,” with a subset of over- differ from other risk factors in requiring a apparent before diabetes. In the Diabetes adverse effect. Studies in Europe (35) and Asia (36) show that the minority of indi- viduals with heart disease have NGT, with a group of studies of ϳ25,000 individuals fect in pre-diabetes in youth involved re- sufficient to ascertain glycemic abnormal- duced insulin secretion (24,25), with IGT ity in this group (37), and that there is less evidence for such an increase in fast- reduced survival in individuals with heart with insulin resistance. Both factors are disease found to have diabetes (38), fur- than fasting glucose predicting all-cause ther suggesting the importance of assess- ing glucose tolerance. In this study, the minority of newly identified diabetic pa- clearly found for fasting glucose. Adjust- but those so treated showed a significant resistance and loss of the first and second ing for fasting glucose, 2-h glucose con- phases of insulin secretion, leading to a tinued to significantly predict increased events (39). Interestingly, a study of indi- the absolute risk was greater for diabetic clinically diagnosed type 2 diabetic chil- dren have positive GAD, islet-associated, treatment, and statins reduced mortality, or islet cell antibodies and tend to have greater loss of insulin secretion and lesser with diabetes because of the greater prev- those without diabetes. Similarly, in this insulin resistance, leading to the same re- alence of the former group, implying that study, revascularization was highly bene- this group could benefit from treatment.
ficial for the diabetic but not for the non- greater insulin resistance and lesser insu- lin secretory deficiency. Data on compli- increase in cancer mortality, a less well- but there is evidence that atherosclerotic complications begin in childhood (28).
pulse wave velocity (a measure of arterial stiffness) in type 2 diabetic children, with the effect of fasting glucose on risk elimi- lesser but still significant increase in obese glycemia with cerebrovascular disease.
nondiabetic children (29), indicating pre- failed to eliminate the association of 2-h increased in people with diabetes and, to a lesser extent, in those with pre-diabetes insulin resistance have increased systolic levels, with evidence of endothelial dys- formed (42). Finally, the risk of recurrent that high 2-h glucose levels carry greater and triglyceride levels among adolescents in NHANES (19). “The big question,” Ar- slanian concluded, “is what is the tempo abnormal fasting glucose “doesn’t make dicting 10-year risk of type 2 diabetes in of progression. . . . In pediatrics it is going any sense,” as those with normal fasting to be highly difficult to answer this ques- english), with age, BMI, waist circumfer- tion.” To stop the progression to diabetes vegetables and fruits, diagnosis of hyper- vene, what the timeline of obesity-related family history of diabetes used to calcu- the magnitude of risk is for a given degree correlate with 10-year diabetes risk (44), lipids, and cigarette use. The increase in likelihood of CVD and mortality (45).
seen at 0 –5 years as at 5–10 and 10 –15 tervention has been shown in the U.S. Di- DIABETES CARE, VOLUME 31, NUMBER 10, OCTOBER 2008 Perspectives on the News
fited. In the DPP, LDL decreased similarly trial would require at least a decade.
with metformin and lifestyle, and for HDL cholesterol and triglyceride levels the life- effective in the highest-risk group, with safe intervention such as lifestyle reduces ongoing benefit for 4 years after the con- clusion of the formal lifestyle intervention placebo group, blood pressure, triglycer- (48); and in the Chinese Da Qing Diabetes “it is going to be very difficult to prove.” gressing to type 2 diabetes. Of those not issues of the impact of pre-diabetes on ne- (49). Based on the differences reported in thirds of the placebo group developed the not a risk factor, as it has not fully been shown to affect the course of renal disease or CVD when taking all other factors into could then be of great benefit, although it with the lifestyle intervention (54). Levels account. Furthermore, in addition to hav- of tissue plasminogen activator, plasmin- ing 20 –25% biologic variability, the as- ogen activator inhibitor-1, and C-reactive says themselves have 5–10% variability, protein similarly showed greatest improve- ment with lifestyle intervention, intermedi- ate improvement with metformin, and little (55). Diabetes prevention does, then, ap- diabetes prevention, he asked, reduce mi- cations Trial appears to be the only study preclinical studies support this effect.
(TRIPOD) study with troglitazone (56)
Bakris noted that the usual upper limit of creatinine, is unlikely to be correct, sug- gesting that, with metformin and lifestyle better cutoff. Albuminuria is strongly as- diabetic retinopathy developing in 1.0 vs.
1.8% and microaneurisms in only 6.9 vs.
(59). Bakris pointed out that the relation- 10.8% of subjects, respectively (50).
is considerably stronger than that of CRP placebo, metformin, or lifestyle modifica- with CVD, such that he did feel this to be tively, with lesser relative but greater ab- solute decreases in stroke and CHD (58).
is an even stronger CVD risk factor (61).
croalbuminuria, with a net 1% increase in tion rate (GFR) a sturdier measure of renal diabetes will be paid later if we don’t do crease with the lifestyle intervention. In anything today.” Is it possible to carry out (DREAM) trial, 9.2% of those receiving
nal failure, the great risk of CKD is its tion—for the statistical certainty to be croalbuminuria, similarly suggesting ben- 0.05 and the trial power to be 90%, 3-, 5-, diabetes are additive in causing cerebro- vascular disease, coronary artery disease, blood pressure, in association to a lesser extent with metformin than with lifestyle or peripheral arterial insufficiency.
modification, with lifestyle modification 5–15%, further increasing the number of participants required to successfully carry out such a study. Also, there may well be a lag period, as suggested by Tuomilehto, groups suggest goal blood pressure levels of over 5 years, beginning at the time of iglitazone, blood pressure similarly bene- DIABETES CARE, VOLUME 31, NUMBER 10, OCTOBER 2008 Bloomgarden
Hoorn Study. JAMA 285:2109 –2113, 2001 ripheral effects causing abnormality of va- 9. Rijkelijkhuizen JM, Nijpels G, Heine RJ, ity of small C-fiber nerves (77). The con- individuals with impaired fasting glucoseis explained by conversion to diabetes: the stated, it appears that with systolic blood Hoorn study. Diabetes Care 30:332–326, blood flow correlates with systolic blood GFR stabilizes at ϳ2 ml ⅐ minϪ1 ⅐ yearϪ1.
the current definition for diabetes rele- vant to mortality risk from all causes and (63a). High-risk populations, particularly nerve fibers in the proximal leg in associ- diseases? Diabetes Care 26:688 – 696, blood pressure control (64). Dietary salt is important for limiting the benefit of RAS- malities improve with lifestyle interven- g/day may decrease the antiproteinuric ef- fect of RAS blockade by half (65), and this is only partially restored with thiazide di- cardial infarction (76), perhaps explain- Risk in Communities Study. Diabetes Care that changes in albuminuria with lifestyle 12. Yudkin JS, Forrest RD, Jackson CA, Ryle leads to reduction in albuminuria (67).
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